Implant with reactive oxygen species scavenging coating

ABSTRACT

A chronically implanted medical device is disclosed that has an outermost layer formed from a conjugate of a polymer with lipoic acid, the conjugate having free 1,2-dithiolane groups. It is contemplated that this layer scavenges reactive oxygen species, i.e. acts as an antioxidant, and thus reduces inflammation and other adverse effects around the implant itself.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/053,532, filed Feb. 25, 2016, which claims priority to U.S.Provisional Patent Application Ser. No. 62/121,177, filed Feb. 26, 2015.That application is hereby fully incorporated by reference in itsentirety.

BACKGROUND

The present disclosure relates to methods of reducing inflammationaround a chronically implanted medical device by coating the device witha polymer/lipoic acid conjugate. This conjugate is particularly usefulfor coating an electrode which is inserted into the brain, asneurodegeneration around the electrode is reduced, thus permittingneural signals to be recorded by the electrode for an extended period oftime.

Neural signal recording failure from chronically implanted neuralelectrodes is a major issue that limits the widespread deployment ofsuch devices for rehabilitation related applications where the recordingof brain signals is useful or necessary. It is widely hypothesized thatglial scar, which is a result of the body's immune response to the“foreign” electrodes, electrically impedes the recording ability of theelectrodes.

Recently, it has been suggested that the presence of electrodes in braintissue creates a chronic inflammatory state which causesneurodegeneration (loss of neuron function) and can lead to implantfailure. Reactive oxygen species (ROS) such as hydroxyl and superoxideradicals may play an important role in the initiation and progression ofchronic inflammation around the electrodes.

It would be desirable to reduce inflammation and neurodegenerationaround chronically implanted devices, such as electrodes, in the brain.More generally, reducing inflammation around a chronically implantedmedical device may be desirable as well.

BRIEF DESCRIPTION

The present disclosure relates to processes and methods for reducinginflammation and neurodegeneration. Briefly, a chronically implantedmedical device, such as an electrode, is coated with a polymerconjugate. The polymer conjugate is formed from a polymer and lipoicacid. The resulting conjugate contains free 1,2-dithiolane groups fromthe lipoic acid, or in other words it is the carboxylic acid portion ofthe lipoic acid that forms a covalent bond with the polymer.

Disclosed in various embodiments are implantable devices, comprising: asubstrate having a surface; and an outermost layer on the surfacecomprising a conjugate of a polymer with lipoic acid, the conjugatecontaining free 1,2-dithiolane groups. In specific embodiments, thedevice can be an electrode.

The polymer may contain sidechains having a terminal epoxy, hydroxyl, oramino group which react with the lipoic acid. The polymer may be acopolymer. The polymer may be formed from a first monomer selected fromthe group consisting of silanes, acrylates, acrylamides, andvinylphenols. The second monomer may be an alkene. In particularembodiments, the polymer is a poly(glycidyl methacrylate) polymer.

In the conjugate of the polymer with lipoic acid, the lipoic acidgenerally reacts with a reactive sidechain and forms a covalent bond. Asa result, the conjugate may be considered a copolymer as well.

Also disclosed are methods of reducing neurodegeneration around anelectrode in a patient, comprising: inserting an electrode into apatient, the electrode having an outermost coating comprising aconjugate of a polymer with alpha lipoic acid, the conjugate containingfree 1,2-dithiolane groups.

In some embodiments, the methods further comprise: inserting a separatestimulating electrode into the patient proximate to the electrode havingthe outermost coating; and sending an electrical signal to thestimulating electrode to enable redox chemistry at the electrode havingthe outermost coating.

The electrode can be inserted into the brain of the patient.

Also described herein are methods of reducing inflammation around animplanted medical device, comprising: coating the medical device with anoutermost layer comprising a conjugate of a polymer with alpha lipoicacid, the conjugate containing free 1,2-dithiolane groups. The coatedmedical device, when implanted, should suffer less inflammation in theregion proximate the medical device due to the coating.

Also disclosed in embodiments herein are graft copolymers formed fromthe reaction of: a polymer having a silane backbone or having epoxysidechains; and lipoic acid. In specific varieties, the polymer is apoly(glycidyl methacrylate) polymer

These and other non-limiting characteristics are more particularlydescribed below.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings, which arepresented for the purposes of illustrating the exemplary embodimentsdisclosed herein and not for the purposes of limiting the same.

FIG. 1 is an illustration of the formation of a polymer/lipoic acidconjugate of the present disclosure.

FIG. 2 is an illustration of the formation of a polymer/lipoic acidconjugate, where the polymer is a siloxane, and the substrate is shown.

DETAILED DESCRIPTION

The present disclosure may be understood more readily by reference tothe following detailed description of desired embodiments and theexamples included therein. In the following specification and the claimswhich follow, reference will be made to a number of terms which shall bedefined to have the following meanings.

Although specific terms are used in the following description for thesake of clarity, these terms are intended to refer only to theparticular structure of the embodiments selected for illustration in thedrawings, and are not intended to define or limit the scope of thedisclosure. In the drawings and the following description below, it isto be understood that like numeric designations refer to components oflike function. Furthermore, it should be understood that the drawingsare not to scale.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “comprising” is used herein as requiring the presence of thenamed components/steps and allowing the presence of othercomponents/steps. The term “comprising” should be construed to includethe term “consisting of”, which allows the presence of only the namedcomponents/steps, along with any impurities that might result from themanufacture of the named components/steps.

Numerical values should be understood to include numerical values whichare the same when reduced to the same number of significant figures andnumerical values which differ from the stated value by less than theexperimental error of conventional measurement technique of the typedescribed in the present application to determine the value.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 2 grams to 10grams” is inclusive of the endpoints, 2 grams and 10 grams, and all theintermediate values).

The term “about” can be used to include any numerical value that canvary without changing the basic function of that value. When used with arange, “about” also discloses the range defined by the absolute valuesof the two endpoints, e.g. “about 2 to about 4” also discloses the range“from 2 to 4.” The term “about” may refer to plus or minus 10% of theindicated number.

The term “alkene” refers to a molecule composed entirely of carbon atomsand hydrogen atoms which contains at least one carbon-carbon double bondthat is not part of an aryl or heteroaryl structure. The alkene moleculemay be linear or branched. Exemplary alkenes include ethylene andpropylene.

The term “hydroxyl” refers to a radical of the formula —OH, wherein theoxygen atom is covalently bonded to a carbon atom

The terms “carboxy” or “carboxyl” refers to a radical of the formula—COOH, wherein the carbon atom is covalently bonded to another carbonatom. It should be noted that for the purposes of this disclosure, acarboxyl group may be considered as having a hydroxyl group. However, itshould be noted that a carboxyl group can participate in certainreactions differently from a hydroxyl group.

The term “amino” refers to a radical of the formula R₁—NHR₂, wherein R₁is a carbon atom, and R₂ is a carbon atom or a hydrogen atom. Forpurposes of this disclosure, an amino group is a primary amino group ora secondary amino group, and can be reacted.

The present disclosure relates to a graft copolymer that acts as ascavenger of reactive oxygen species (ROS). The graft copolymer isformed by conjugating a polymer with lipoic acid, where the1,2-dithiolane group of the lipoic acid remains free. This graftcopolymer is applied as a coating to a medical device, such as anelectrode.

Lipoic acid (LA) and its redox couple, dihydrolipoic acid (DHLA), aredepicted below:

Lipoic acid (LA, thioctic acid, 1,2-dithiolane-3-pentanoic acid) andDHLA both act as antioxidants by reacting with ROS such as hydrogenperoxide, hydroxyl radicals, singlet oxygen, hypochlorous acid (HOCl),peroxynitrite (ONOO⁻), and superoxide radicals. They can alsorecycle/regenerate other antioxidants such as vitamin C, thioredoxin,and glutathione, which in turn can recycle vitamin E.

Microglia form the first layer of cells that surround the neuralelectrode. Microglia are macrophage-type cells that secrete ROS andcytokines. These in turn attract other cells, such as astrocytes, to theelectrodes and thus lead to the formation of glial scar around theneural electrodes. As a result, the same signal to be read by theelectrode changes over time.

Placing a coating of LA/DHLA on the surface of the implanted electrodeis contemplated to provide rapid scavenging of ROS in the immediatevicinity of the electrode, thus reducing the immune response. Thus, anelectrode, or generally any medical device intended to be chronicallyimplanted, can be coated so that its outermost surface is formed fromthe polymer conjugate/graft copolymer of the present disclosure.

In addition, LA/DHLA form a redox pair. The reduction potential for theLA/DHLA couple is reported to be between −320 mV and −290 mV. LA canaccept electrons and be reduced to DHLA, while DHLA can react with afree radical and be oxidized back to LA. Thus, it is possible toregenerate the desired form of LA/DHLA using stimulating electrodes thatprovide/remove electrons as needed, or by using the same electrode uponwhich the LA/DHLA is coated. For purposes of this disclosure, anyreference to lipoic acid should be construed as also referring todihydrolipoic acid.

The coating/outermost layer is formed from a conjugate of a polymer withlipoic acid. This polymer conjugate can also be considered a graftcopolymer. The conjugate is formed by the reaction of the polymer withlipoic acid.

Generally, the polymer contains sidechains that can react with thecarboxyl group of lipoic acid. The sidechains include a terminal epoxygroup, hydroxyl group, or amino group, all of which can react with acarboxyl group. In particular, the reaction of a carboxyl group with ahydroxyl group will result in an ester linkage, while the reaction of acarboxyl group with an amino group will result in an amide linkage.

The polymer can be a homopolymer, or can be a copolymer formed from twoor more monomers. In particular embodiments, the polymer can be formedfrom a first monomer selected from the group consisting of acrylates,acrylamides, silanes, and vinylphenols. If the polymer is a copolymer,the second monomer can be another one of the first monomers, or can bean alkene such as ethylene, propylene, etc.

Acrylate monomers contain a vinyl group directly attached to a carbonylcarbon, where the carbonyl and a reactive hydroxyl group. Exemplaryacrylate monomers include acrylic acid, methyl acrylate, methylmethacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate,hydroxyethyl methacrylate, butyl acrylate, and butyl methacrylate.Acrylamides contain a vinyl group and an amide group. An exemplaryacrylamide is prop-2-enamide. Silane monomers can be used to form asilane coating on the substrate and also provide a terminal sidechaingroup for the lipoic acid to react with. Exemplary silanes can includetrimethoxy[3-(methylamino)propyl]silane or3-hydroxypropyltrimethoxysilane, which can be used to form siloxanepolymers. Other monomers that might be suitable for producing thepolymer include vinyl alcohol and ethylene imine.

In more specific embodiments, the polymer that is used to form theconjugate includes a terminal epoxy group which is reacted with thecarboxyl group of the lipoic acid. In particular embodiments, thepolymer is poly(glycidyl methacrylate), herein abbreviated as PGMA. FIG.1 is a depiction of a chemical reaction showing how the conjugate isformed by the reaction of a PGMA homopolymer with lipoic acid (LA) toobtain a graft copolymer. The two monomers of the conjugate reflect thefact that the LA does not react with all epoxy groups of the PGMAhomopolymer. The molar ratio of monomers that have not reacted tomonomers that have reacted is indicated by a:b. The ratio of a:b canrange from 1:99 to 99:1, and is desirably 50:50 or higher (with more LAsidechain being preferred).

More generally, the polymer conjugate of the present disclosure can berepresented by Formula (I) below:

where M₁ and M₂ are independently a monomer; L is a divalent linkinggroup; and a and b represent the molar percentage of each monomerpresent in the polymer conjugate, where a+b=100 molar percent. It isnoted that the 1,2-dithiolane group of the LA is free at the end of thesidechain, and is able to react with ROS.

FIG. 2 is an illustration of a substrate upon which is a conjugateformed from a siloxane polymer having LA conjugated therefrom.

As previously mentioned, LA/DHLA form a redox pair. More generally, thepresent disclosure can be considered to be directed to the use of aconjugate of a polymer with any molecule that forms a redox pair and canscavenge reactive oxygen species. Lipoic acid and dihydrolipoic acid areone example of such a molecule.

The following examples are provided to illustrate the devices, polymerconjugates, and methods of the present disclosure. The examples aremerely illustrative and are not intended to limit the disclosure to thematerials, conditions, or process parameters set forth therein.

Examples

1 gram of poly(glycidyl methacrylate) (PGMA) was dissolved in 10 mL ofdimethyl sulfoxide in a 3 neck round bottom flask fitted with a magneticstirrer, gas inlet, and a condenser. Once the polymer was dissolved,0.25 grams of lipoic acid and 0.03 grams of t-butyl ammonium bromide(catalyst) were added and stirred at room temperature for 24 hours underan inert argon atmosphere. The product obtained was precipitated frommethanol and dried in vacuum oven at a temperature of 40° C. for 24hours. The product was characterized by acid value titration. 48% of thestarting 0.25 grams of lipoic acid was found to be grafted onto thePGMA.

The present disclosure has been described with reference to exemplaryembodiments. Obviously, modifications and alterations will occur toothers upon reading and understanding the preceding detaileddescription. It is intended that the present disclosure be construed asincluding all such modifications and alterations insofar as they comewithin the scope of the appended claims or the equivalents thereof.

1. A method of reducing neurodegeneration around an electrode in apatient, comprising: inserting an electrode into a patient, theelectrode having an outermost coating comprising a conjugate of apolymer with alpha lipoic acid, the conjugate containing free1,2-dithiolane groups.
 2. The method of claim 1, further comprising:inserting a separate stimulating electrode into the patient proximate tothe electrode having the outermost coating; and sending an electricalsignal to the stimulating electrode to regenerate the conjugate.
 3. Themethod of claim 1, wherein an electrical signal is sent to the electrodeto provide electrons for regenerating the conjugate.
 4. The method ofclaim 1, wherein the electrode is inserted into the brain of thepatient.
 5. The method of claim 1, wherein the polymer containssidechains having a terminal epoxy, hydroxyl, or amino group which reactwith the lipoic acid.
 6. The method of claim 1, wherein the polymerincludes a first monomer selected from the group consisting ofacrylates, acrylamides, silanes, and vinylphenols.
 7. The method ofclaim 6, wherein the polymer includes a second monomer which is analkene.
 8. The method of claim 1, wherein the polymer is a poly(glycidylmethacrylate) polymer.
 9. The method of claim 1, wherein the conjugatehas the structure of Formula (I):

where M₁ and M₂ are independently a monomer; L is a divalent linkinggroup; and a and b represent the molar percentage of each monomerpresent in the polymer conjugate, where a+b=100 molar percent.
 10. Amethod of reducing inflammation around an implanted medical device,comprising: coating the medical device with an outermost layercomprising a conjugate of a polymer with alpha lipoic acid, theconjugate containing free 1,2-dithiolane groups.
 11. The method of claim10, wherein the polymer contains sidechains having a terminal epoxy,hydroxyl, or amino group which react with the lipoic acid.
 12. Themethod of claim 10, wherein the polymer includes a first monomerselected from the group consisting of acrylates, acrylamides, silanes,and vinylphenols.
 13. The method of claim 12, wherein the polymerincludes a second monomer which is an alkene.
 14. The method of claim10, wherein the polymer is a poly(glycidyl methacrylate) polymer. 15.The method of claim 10, wherein the conjugate has the structure ofFormula (I):

where M₁ and M₂ are independently a monomer; L is a divalent linkinggroup; and a and b represent the molar percentage of each monomerpresent in the polymer conjugate, where a+b=100 molar percent.
 16. Amethod of reducing neurodegeneration around an electrode in a patient,comprising: inserting an electrode into a patient, the electrode havingan outermost coating comprising a conjugate of a polymer with amolecule, wherein the molecule is a redox pair and can scavenge reactiveoxygen species.
 17. The method of claim 16, wherein the polymer containssidechains having a terminal epoxy, hydroxyl, or amino group which reactwith the lipoic acid.
 18. The method of claim 16, wherein the polymerincludes a first monomer selected from the group consisting ofacrylates, acrylamides, silanes, and vinylphenols; and wherein thepolymer includes a second monomer which is an alkene.
 19. The method ofclaim 16, wherein the polymer is a poly(glycidyl methacrylate) polymer.20. The method of claim 16, wherein the conjugate has the structure ofFormula (I):

where M₁ and M₂ are independently a monomer; L is a divalent linkinggroup; and a and b represent the molar percentage of each monomerpresent in the polymer conjugate, where a+b=100 molar percent.